Compounds useful as antidepressive agents

ABSTRACT

Compounds having the structural formula   AND THERAPEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, WHERE THE PYRIDINE NUCLEUS IS BOUND IN ORTHO-, META- OR PARAPOSITION TO THE ADJACENT CARBON ATOM AND WHERE R1 is selected from the group consisting of H, and Br, pharmaceutical compositions containing such a compound suitable for use as an anti-depressant and methods for preparing such compounds, including the formation of an intermediate com

United States Patent [191 Berntsson et al.

[ COMPOUNDS USEFUL AS ANTIDEPRESSIVE AGENTS [75] Inventors: Peder Bernhard Berntsson,

Frolunda; Per Arvid Emil Carlson, Goteborg; Hans Rudolf Corrodi, Askim, all of Sweden [73] Assignee: Aktiebolaget Hassle, Goteborg,

Sweden [22] Filed: Jan. 7, 1974 [21] Appl. No.: 431,123

Related US. Application Data [62] Division of Ser. No. 247,101, April 24, 1972,

abandoned.

[30] Foreign Application Priority Data 8/ 1957 Germany 260/296 R Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Brumbaugh, Graves, Donohue & Raymond Dec. 23, 1975 [57] ABSTRACT Compounds having the structural formula R C-CHCH2N\ and therapeutically acceptable acid addition salts thereof, where the pyridine nucleus is bound in ortho-, metaor para-position to the adjacent carbon atom and where R is selected from the group consisting of H, and Br, pharmaceutical compositions containing such a compound suitable for use as an antidepressant and methods for preparing such compounds, including the formation 'of an intermediate compound having a formula 4 Claims, No Drawings 1 ,2 COMPOUNDS USEFUL AS ANTIDEPRESSI V li p AGENTS CH The present application is a divisional application of C=CHCH2NZ 3 v application Ser. No. 247,101, filed on Apr. 24, 1972. CHB

The present invention relates to new compounds having therapeutic activity. The invention further comprises pharmaceutical preparations containing at least one of the compounds, the medical use of the comp n and a pr f p paring t e C P have an antidepressive effect, cf J. Med. Chem. 14,

The antidepressive agents having the most wide- 161 1 (1971-). From the literature compounds having spread, clinical use are the tricyclic tertiary amines the formula imipramine having the structure formula l5 X I CH \'CHCH;CH N v1 3 crr CH2CH2CH2-N\ I 3 g and amitriptyline having the structure formula wherein X is chlorine or bromine and R is hydrogen or methyl, are described as having an antihistaminic ef- I feet, and antidepressive effect, cf U.S. Pat. No.

3,423,510. The compound of formula VI wherein X is CH bromine and R is methylis calied brompheniramine in CH-CH CH II 3 Table 1 below. These compoiindsillustrated ,by for- \CHs mula V above have, however, the serious-side-effect of being anxiety developing and also orthostatism Secondary amines such as desipramine having the developing. structure formula A main object of the present invention is to obtain new compounds having a goodjantidepressive effect. A further object of the invention is to obtain compounds having an antidepressive effectwhich does not produce orthostatism, anticholinergic effects or arrhythm'ogenic N ,effects. Further objects of the'inventionwill be evident 3H 4 0 from the following description Accordin to the 'resentinvention it hasbeen found cn cn cr-i N III 8 P cH that compounds of theformul'a, 2

and nortriptyline having the structure formula v 1 CH3 c=cncn it VII H i CH3 CHCH2CH2 N\ IV CH3 I are used to a somewhat less extent. All these substances have, however, side effects which are not desired in therapeutic use such as orthostatism, anticholinergic h in the yridine nucleus isbound in ortho, meta or effects and above all, an arrhythmogenic-heart arrhythpara-position to the next carbon atom and wherein the mic developing effect when administered in large doses b rit em R is lected from; the group consisting of to old patients. The secondary amines, such as desipra- 0 hydrogen, or bromine, and therepeutically acceptable mine and nortriptyline have also the known effect of acid addition salts thereof, are {potently active antidedeveloping anxiety in many depressed patients. Morepressive, depression reducting agents, which do not over, all the substances mentioned show the drawback give troublesome side effects such as anxiety, orthostatthat the antidepressive effect starts first after some i m and heart arrhythmias, as do the clinically most weeks of treatment. This delayed effect must be used tricyclic agents such as imipramine, desipramine, cribed to the fact that all the substa'iices have a low amitriptyline gnd nortriptyline, and the compounds antidepressive activity. Further, it is w n from" the known frornlthe liteiture, such as those of formula V. literature that Certain p 'Y Xh p i Illustrative examplesof the compounds of the invenl-enes, such as the compound having 'theforrriula' i tion are cu -,--;s k CICHCH N 3 H 102/09 2 CH v I H iOO/04 CH I "c:c-HcH N 3 H 99/88 cu i l I 1 CH 8r c'=cHcH N 3 cH N\ I Br m i z M I CH. Br c=cHcH 3 4 -CH 3 The preferred compounds of are the I The compounds of the invention may be prepared compounds having code numbersHj l"0 2/) 9', H l02/1 0 according to processes known per se. a suitable process and H 100/04. p is the dehydration of a compound of the formula The dehydration of the compound of formula IX may for example be done by means of concentrated sulphuric acid andheating of the reaction'mixture to a high temperature about 165 to 175C. The"dehydration ofthe cornpound of'forrnula'lX may also be done by means of other types of acid-catalysis, such as for example by means of hydrochloric acid, HCl, phos phoric acid, H PO Potassium hydrogen sulphate, KHSO oroxalic acid (COOH), Other methods for the dehydration of the compound offormulalX -'to form a compound-of the formula X are dehydration using phosphoroxichloride POCl in pyridine, and de hydration with thionyl chloride, SOCl in pyridine. Also a catalytic dehydrationof the compound of the formula IX may be used. The dehydration is in this case carried out at a temperature of about 300 to 500C using a catalyst such as kaolin, aluminium or aluminium oxide, Al O as a-cataly'st; 1 Starting materialsof the formula lX may be prepare in a number of ways, such as by reacting'a compound of theformula in which formulasR hasthemeanings indicated-above 60 and the lithium atom is bound in.orth.o-, .metaor paraposition to the pyridine nucleus; i

The'final compounds according'to the'iiive'ntion may exist incisor trans-configuration or E and l-configuration according to the lUPACmomencla tureandthe therapeutic effect cannot significantly be attributed excluxively to one of these forms but can to a greater or less extent be attributed to on'eor'both' of th' cis-form and the trans-form. H v v ,1 I I In clinical practice the compounds of the present invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical prepara- The intermediates of formula ILX, where R ,has the meaning given above and-where the pyridinen'ucleus is bound in ortho-, meta or para-position to the adjacent carbon atom, and thereapeutically acceptable, acid addition salts thereof, are a further embodiment of the present invention.

tions comprising the active ingredient .ei ther asafree base or as a pharmaceutically acceptable acid addition salt, e.g., the .hydro'chloride, lactate, acetate, oxalate, and the like, in association with a pharmaceutically acceptable carrier which may be a,solid,semisol id or liquid diluent or an edible capsule. I I

Usually the active substance will constitutebetween 0.1 and 95 by weight of the preparation, morespecifically between 05 and 20 by weight for preparations intended for, injection and between OJ and 50 by weight for preparations suitable for oral administration To produce pharmaceutical preparations in the form of dosage units for oral applicationcontaining a compound of the invention in the form of th free base, or a pharmaceutically aeceptable's alttliereof, the active ingredient may be mixed with a solid, pulverized carri'erj for example, lactose, saccharose, sorbitol, mannitol, starch such as potato starch, corn starch,v maize starch orjamylopectin, a cellulose derivative or gelatin, andalso may include lubricants .such as magnesium or vcalcium stearat'e or. a Carbowax or other polyethylene glycol waxesand eompressed to form tablets or centers for dra gee s. lf d'ragees' are required, the centers may be coated, for example, with concentrated sugar solutions which" may contain gum arabic,,talc;and/or titanium dioxide, or alternativelywith a lacquer dissolved in *e'asily yolatile organic" solvents or mixtures of organic solvents. Dyestuffs can be added to'the'se coatings. For

thep'reparation of soft gelatin capsules (pearl-shaped closed eapsuleslcqnsisting of gelatin and, for example, glycerol, or similar closed capsules," the "active .substance maybe admixed with a Carbow ax. Hard-gelatin capsules may contain granulates of the active substance rose, sorbitol, mariiiitol, starches, for example, potato with'solid, pulverized carriers such as lactose, sacchastarch, corn starch or amylopectin, cellulose derivatives or gelatin, and may also include magnesium stearate or stearic acid. Dosage units for rectal application may be in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatin rectal capsules comprising the active substance in admixture with a Carbowax or other polyethylene glycol waxes.

Liquid preparation for oral application may be in the form of syrups, suspensions or emulsions, for example, containing from about 0.1% to 20% by weight of active substance, sugar and a mixture of ethanol, water, glycerine, propylene glycol and any flavouring agent, saccharine and/or carboxy methyl cellulose as a dispersing agent.

For parenteral application by injection the preparations may contain an aqueous solution'of a water-soluble pharmaceutically acceptable salt of the active substance preferable in a concentration of 0.5 to 10% optionally a stabilizing agent and/or buffer substance in an aqueous solution. Dosage units of the solution may advantageously be enclosed in ampoules.

Suitable daily doses of the compounds of the invention for therapeutic treatment are to 500 mg for peroral administration, preferably 50 to 250 mg, and 1 to 100 for parenteral administration, preferably to 50 mg.

BIOLOGICAL EFFECT It is impossible to produce depression in test animals by experimental procedures. In order to test the antidepressive effect of new substances, biochemicalpharmacological test methods have to be carried out. Such a test method which seems to give such indication of the antidepressive effect of a compound, which effect corresponds quite well with the clinically observed effect, has been worked out and is described in European Journal of Pharmacology, 5, 367-373, (1969) and European Journal of Pharmacology, 5, 357-366, (1969). This test method measures the ability of a compound to block the depletion of noradrenaline in the brain and heart which is induced by an injection of 4,a-dimethyl-m-tyramine, and the ability of the compound to block the depletion of S-hydrOXy-tryptamine in the brain, which is induced by an injection of 4- methyl-a-ethyl-m-tyramine. Especially secondary amines of the type desipramine and nort'riptyline are substances which block the depletion of noradrenaline in the brain and heart, but they have the serious side-effect of producing anxiety. The blocking of the depletion of noradrenaline in the brain'and heart which is caused by these compounds probably also induces the ortho-statism. Actually, the depression-alleviating effect of a substance seems to be related to the block of the depletion of S-h'ydroxytryptamine by 4-methyl-aethyl-m-tyramine- As shown below it'has surprisingly been found that the compounds'of'the invention have a strongly blocking effect on the liberation of S-hydrOXy-trypt'amine, which is induced by 4-methyl-a-ethyl-m-tyramine, while the ability of the compounds to block the depletion of noradrenaline, which is induced by 4-a-dimethylm-tyramine is lacking completely or is very weak. Further, the compounds of the invention differ from all tricyclic antidepressive agents hitherto used in that they have a much lower heart arrhythmia inducing effect than the tricyclic agents hitherto used. Compounds of the type described in Journal of Medicinal Chemistry 14, 161-164, (1971) have certainly an antidepressive effect, but this antidepressive effect is low compared to the effect of the compounds of the invention, and these known compounds, which are illustrated by compound V above are also substantially able to block the depletion of noradrenaline in the brain and heart induced by 4-a-dimethyl-m-tyramine, which in man leads to said unwanted side-effects, anxiety and probably also leads to orthostatism. The compounds described in the US. Pat. No. 3,423,510 and illustrated by compound VI above, are described as antihistaminic and antidepressive agents.

A pharmacologic comparison between the compounds of the invention and previously used tricyclic antidepressive agents and compounds described in the literature is given below.

Blocking effect on the depletion of S-hydroxy-tryptamine induced by 4-methyl-a-ethyl-m-tyramine B c-a inhibition A the amount of 5-hydroxy-tryptar'nine (ng/g) in the brain after the administration of the test substance and 4-.methyl-a-ethyl-m-tyramine.

B the amount of S-hydroxy-tryptamine (ng*/g) in the brain after the administration of 4-methyl-a-ethyl-mtyramine.

*nanograms (10' grams) C the amount of S-hydroxy-tryptzimine (ng/g) in the brain after the administration of the test substance. The effective dose which inhibits the depletion of S-hydroxy-tryptamine to 50% (ED is the calculated by a regression analysis. The test results are given in Table 1 below.

1.2 Mice The substance to be tested is injected intraperitoneally in mice. 30 minutes later 100 mg/kg of 4-methyl-aethyl-m-tyramine is injected intraperitoneally. minutes later the test substance is administered again in an amount corresponding to half the original dose and 30 minutes later 4-methyl-a-ethyl-m-tyramine mg/kg) is administered. 2 hours later the animals are killed and the amount of 5-hydroxy-tryptamine in the brain is determined.

The percental inhibition of the depletion of 5- hydroxy-tryptamine and the ED is determined in the same way as under 1.1. A detailed description of the method is givenin European Journal of Phamacology 5, 357-366, (1969). The test result is given in Table 1 below.

The blocking effect of the depletion of noradrenaline induced by 4,a-dimethyl-m-tyramine The substance to be tested is injected intraperitoneally in mice (10 mg/kg). 30 minutes later 4,a-dirne'thylm-tyramine is administered (12.5 mg/kg). 90 minutes later half the original dose of test substance mg/kg) is administered to the animals and 30 minutes later 4,a-dimethyl-m-tyramine (12.5 mg/kg) is administered. 2 hours later the animals are killed and the amount of noradrenaline in the brain and the heart is determined. Animals treated with the test substance only and with 4,a-dimethyl-m-tyramine only respectively and untreated animals are used as controls.

. the testsubstance. The .testresult is given in Table 1 below.

i The heart arrhythmia inducing effect A solution of the test substance is constantly and slowly infused into nembutal anesthetized rats and the electrocardiograms of the animals are observed. After a certain time an irregular heart rhythm occurs, which becomes more serious and finally leads to a ventricular fibrillation, whereby the animals die. The accumulated dose which is necessary to' induce ventricular fibrillation is given in Table 1 below.

Table l Blocking 'effect on the depletion of S-hydrQXy-tryptamine induces by 4-methyl-a-ethyl-m-tyramine. Blocking effect on the depletion of noradrenaline induced by 4,41-dimethyl-m-tyramine and arrhythmia inducing effect.

Blockage of the depletion i of S-hydrortytryptamine induced by 4-methyl-a-ethyl-mtyramine ED, mg/kg Compound Tested Blockage of the depletion of noradrenaline in mice induced by 4,01- dimethyl-m-tyramine. Percentage inhibition after injection of mg/kg bodyweight of test substance i.p.

Dose (mg/kg bodyweight i.p.) which induces ventricular fibrillation at constant infusion mice imipramine 25 amitripytyline l4 chloroimipramine 7.5 brompheniramine 7.2 l-p-bromophenyl-'-phenyl- 3-dimethylamino-propene (l) l.l-diphenyl-B-dimethylaminopropene (l) l-p'chlorophenyll -phenyl- 3-methylamino-propane H 100/04 4 H l02/09 3.5 H 102/10 5 H 99/88 4 The percental inhibition of the depletion of nor- I I inhibition 100 A the amount of noradrenaline (ng/g) in the brain and heart, respectively, after administration of test substance and 4,a-dimethyl-m-tyramine. I B the amount of noradrenaline (ng/g) in thebrain and heart, respectively, after the administration of g 4,a-dimethyl-mtyramine. C The amount of noradrenaline (ng/g) in thebrain and heart, respectively, after the administration of I As evident from the test values of Table l the compounds tested of the invention have a strong blocking effect on the depletion of j hydroxy-tryptamine. vinduced by 4-methyla ethy l-m tyramine compared to the reference substances, while the effect of the compounds of the invention on the depletion of noradrenaline induced by 4,a'-dimethyl-m-tyramine is low. That dose in mg/kg b'odyweight i'.'p., which induces ventricular fibrillation at a constantinfusion is in the same way considerably higher" for "the compounds tested of the invention compared to thereference substances, which means' that 'the compounds of the invention have a consideia'bly lower heat arrhythmia inducing effect than the reference substances.

The preparation of the compounds of the present invention is illustrated by the following Examples.

EXAMPLE 1 The preparation of (E)- and (Z)-3-(4-bromophenyl-3-(2-pyridyl)-dimethylallylamine dihydrochloride.

orated, and the residue is dissolved in acetone. After 24 hours the precipitate formed is filtered off. Yield 15 g (E')-3-(4'-bromophenyl)-3-(2-pyridyl)dimethylallylamine dihydrochloride (H 100/03) Mp 160C.

The starting material 1-(4'-bromophenyl)-3-(N,N- dimethylamin)-1 -(2"-pyridyl)-propanol was prepared in the following way:

97 "g of 1-(;t-bromophenyl)-3-(N,N-dime thylamino)-1-(2'-pyridyl)-propanol (H 94/96) are dissolved in 300 ml of 85% H 80; and heated at 170C for minutes. Thereafter the reaction mixture ispoured into 1 l. of water, which is made alkaline by means of 10 N NaOH and is extracted with 2 X 250 ml of ether, which is dried, treated with active carbon and evaporated. The product obtained is dissolved in 250 ml of ether and dry HCl is introduced. The pre'cipita te obtained is filtered off and recrystallized from ethanol 99.5% Yield 40 got" (Z)-3- (4-t romophenyl)-3-(2"- pyridyl)dimethylallylamine dihydrochloride (H 100/04) Mp 195C.

The mother liquor from the recrystallization is evap- CH (CH3) aZHCl N Li To 50 g of n-butyl lithium in 0.5 l of dry ether, 23.7 g of 2-bromopyridine is added at -40C as quickly as possible without raising the temperature. After finishing the addition the mixture is stirred for another 30 minutes. Than 1.5 l of dry ether is added and then 197 g w-dimethyl-amino-4'-bromopropiophenone is added so that the temperature does not exceed 40C. The cooling is discontinued and the mixture is stirred during the night, whereupon the reaction mixture is poured onto ice and diluted l-lCl, and is then washed with some methylene dichloride. Thereafter the aqueous phase is made alkaline and is extracted with ether, which is dried and evaporated. The residue is recrystallized from petroleum ether at 4060C. Yield 98 g of 1-(4'- e213 bromophenyl)-3;(N,I{-dimethylamino)-l 62"" py yU-WQP Z--Mp.859 "EXAMPLE 2} i The preparation of t J 3-(4'-bromophenyl)-3-(3"-pyridyl)-dimethylallylamine dihydrochloride.

thylamino)-1-(3"-pyridyl)-propanol are dissolved in.

15 ml of 85% H 80, and heated at 170C for 10 minthemix-ture is stirred for another 30 minutes- 28.7 g of *m1dimethyIaminO-4' bromopropiophenone' is added in "r-such a. way .thatthe temperature" does not exceed 40C. The coolingis discontinued and, the mixture' is utes. The reaction mixture is poured into 60 ml of Theprecipitate obtained is filtered off..;Yield 1.2 g'of 3-)4-brornophenyl)'-3(3"-pyridyl)-dimethylallyla-' mine dihydrochloride (11 102/09 Mp 193C.

Thestarting material."1 (4'-bromophehyl)J-(Ihhlstirred during the night whereupon the reaction mixture is poured onto ice and diluted HCl. The aqueous phase is washed with methylene dischloride whereupon it is made alkaline with N NaOH and is extracted with ether. The ether phase is dried withNa SO puritied with activated carbon and evaporated. The residue recrystallized from diisopr opyle ther. Yield 3 g of "1-(4-bromophenyl)-3 N,N dimethylamino)-1-(4 pyridyl)propanol. Mp 120C. The following compounds werejprepared in a manner analogously with the process of Examples 1 to 3.

dime'thylamino)-l-(3 pyridyl)-propanol is prepared I in the following way. A

To 9 of n-butyllithium in200'rnl of dry ether 20 g of 3-br'omop yridine is added. as quickly as possible at 40C without raising the temperature. When the addition is finished the mixture is stirred for another minutes. Thereafter 32.5 g of ai-dime'thylamino-4- bromopropiophenone is added in such a way that the temperature does not exceed 40C. The cooling is discontinued and the mixture is stireed during the night whereupon the reaction mixture is poured onto ice and diluted l-lCl, which is washed with ether and is extracted with 20 ml of methylene dichloride. The methylene dichloride is dried and evaporated. The crystals.

are dissolved in water, which then is made alkaline with a solution of Na CQ jis extracted with ether, dried, and evaporated and recrystallized from isopropyl ether, petroleum ether 1:1. Yield 4 g of 1-(4'-bromophenyl)- 3-(N,N-dimethylamino)-1-(3"-pyridyl)-propanol. Mp. 67C.

.EXAMPLE-3 t The preparation of3 -(4'-bromophenyl)-3-(4"-pyridyl)-dirnethylallylamine dihydrochloride i l-(4"-.pyridyl)-propanol are dissolved in 10ml of 85% H and is heated at 170C for 15 min. The reaction mixture isthen poured into ice water, which .is made alkaline with 10 N NaOH and is extractedwith ether..

11 "C CHcl-l blmfl t 2x01 Example Compound I a 'Meltin point (code number) R f E 1 1H /04 195 l H l00/03 H 4 H 99/88 Br 136 2 H 102/09 H 193 3 H lO2/l0 H Following examples illustratehow the compound of the present invention may be included into pharmaceutical preparations.

' y EXAMPLE5[ Preparation of soft gelatin capsules.

500 g of active substance were mixed with 500 g of corn oil, whereupon the mixture was filled in soft gelatincapsules, each capsule-containing 100 mg of the mi'xture'(i.e..5,0v mg of active-substance). i

, p I XAMPLE .6. I Y Preparation of soft gelatin capsules.

i 500 g of active substance'were mixed 700 g of peanut oil, wherein themixtur was filled in soft gelatin capsules, each capsule containing 125 mg of the mixture (i.e. 50 mg of active substance).

EXAMPLE 7 Preparation of tablets.

50 kg of active substa ce were mixed with 20 kg of silicic acid of the trademark Aerosil. 45 kg of potato starch and 50 kg of lactose were mixed therewith and the mixture was moistened with a starch paste prepared from kg of potato starch and distilled water, whereupon the mixture was granulated through ,a sieve. The granulate was dried andsieved, whereupon 2 kg of magnesium stearate was mixed into it. Finally the mixture was pressed into tablets each weighing 172 mg.

I EXAMPLE 8 Preparation of an emulsion;

100g of active substance were dissolved in 2500 g of peanut oil. From the solution 'thus obtained, 90 g of gum arabic, aroma and colouring agents (q.s.)and

2500 g of water an emulsion was prepared EXAMPLE 9 i Preparation of a syrup.

100 g of active substance were dissolved in 300 g of 95 ethanol, whereupon 300 g of glycerol, aroma and colouring agents (q.s.) and 1000 ml of water were mixed therein. A syrup was obtained.

EXAMPLE 10 Preparation of a solution 100 g of active substance were dissolved in 2000 g of polyoxyethylene sorbitan monooleate, whereupon flavouring agents and colouring agents (q.s.)and water to 5000 ml were mixed therein. A drop solution was obtained.

EXAMPLE 11 Preparation of effervescing tablets.

100 g of active substance, [40 g of finely divided citric acid, 100 g of finely divided sodium hydrogen carbonate, 3.5 g of magnesium stearate and flavouring agents (q.s.) were mixed and the mixture was pressed into tablets each containing 100 mg of active substance.

EXAMPLE 12 Preparation of a drop solution.

100 g of active substance were mixed with 300 g of ethanol, whereupon 300 g of glycerol, water to 1000 ml, aroma and flavouring agents (q.s.) and 0.1 N sodium hydroxide solution (to pH 4.5 to 5.5) were added while stirring. A drop solution was obtained.

EXAMPLE 13 Preparation of a sustained release tablet.

200 g of active substance were melted together with 500 g of stearic acid and .50 g of carnauba wax. The mixture thus obtained was cooled and ground to a particle size'of at most 1 mm in diameter. The mixture thus obtained was mixed with 5 g of magnesium stearate and pressed into tablets each weighing 305 mg. Each tablet thus contains 200 mg of active substance.

We claim:

1. A method for treating depression in man, characterized by the administration to a subject suffering from symptoms of central nervous system depression of a compound having the structural formula or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier. l

3. A pharmaceutically preparation according to claim 2, wherein the preparation is in a form suitable for oral administration in dosage units adapted to provide a dose of 50 to 250 mg per day.

4. A pharmaceutical preparation according to claim 2, wherein the preparation is a form suitable for parenteral administration in dosage units adapted to provide a dose of IO to mg per day.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION .PATENT N0. 3,928,613

DATED 1 December 23, 1975 INVENTO I Berntsson et al.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 16, claim 1, lines 6-20, the formula should read C CH CH N Signed and Scaled this Thirtieth Day of November 1976 [SEAL] A I test:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner oj'latents and Trademarks 

1. A METHOD FOR TREATING DEPRESSION IN MAN, CHARACTERIZED BY THE ADMINSISTRATION TO A SUBJECT SUFFERING FROM SYMPTOMS OF CENTRAL NERVOUS SYSTEM DEPRESSION OF A COMPOUND HAVING THE STRUCTRUAL FORMULA
 2. A pharmaceutical preparation for treating depressive conditions containing as an active substance, in dosage units containing an amount effective to treat symptoms of central nervous system depression, a compound having the structural formula
 3. A pharmaceutically preparation according to claim 2, wherein the preparation is in a form suitable for oral administration in dosage units adapted to provide a dose of 50 to 250 mg per day.
 4. A pharmaceutical preparation according to claim 2, wherein the preparation is a form suitable for parenteral administration in dosage units adapted to provide a dose of 10 to 100 mg per day. 